Genetic variation influences the absorption and efflux of drugs in the intestine, the metabolism of drugs in the liver and the effects of these drugs on their target proteins. Indeed, variations in genes whose products have a role in the pathophysiology of nonmalignant gastrointestinal diseases, such as IBD, have been shown to affect the response of patients to therapy. This Review provides an overview of pharmacogenetics in the management of nonmalignant gastrointestinal diseases on the basis of data from clinical trials. Genetic variants that have the greatest effect on the management of patients with IBD involve the metabolism of thiopurines. Variation in drug metabolism by cytochrome P450 enzymes also requires attention so as to avoid drug interactions in patients receiving tricyclic antidepressants and PPIs. Few genotyping tests are currently used in the clinical management of patients with nonmalignant gastrointestinal diseases, owing to a lack of data from clinical trials showing their effectiveness in predicting nonresponse or adverse outcomes. However, pharmacogenetics could have a beneficial role in enabling pharmacotherapy for nonmalignant gastrointestinal diseases to be targeted to the individual patient.